What is new in tremor research?

Orthostatic tremor:

The NTF includes a very active group interested in or impacted by orthostatic tremor.

Primary orthostatic tremor (POT) is a fast (13-18 cycles per second) tremor of the legs that occurs on standing. It typically causes unsteadiness and may be associated with mild Parkinsonian features. As the condition progresses it may cause gait related disability.

Espay and colleagues recently published their preliminary observations on the effect of deep brain stimulation (DBS) on two patients with orthostatic tremor. The target for the electrode placements in the brain was the ventral intermediate nucleus of the thalamus, which is traditionally used to control other types of tremor, including essential tremor.

In the paper, the authors describe two female patients (aged 73 and 67 years) with longstanding POT who have marked disability of stance and gait. One patient receives unilateral and the other bilateral nucleus ventralis intermedius DBS.

Initially the results were encouraging, as both patients derived clinical benefits. These were maintained 18 months after surgery in the patient treated with bilateral ventralis intermedius DBS (i.e. the electrodes were placed in the thalamus on both sides of the brain). However, in the other patient treated with unilateral DBS the benefits were lost three months after surgery.

The tremor characteristics (coherence and frequency which were detected by EMG attached to the patients’ muscles to record the tremor) were unaltered by ventralis intermedius DBS, indicating that this form of surgery weakens the severity of orthostatic tremor, whilst leaving the main characteristics of the tremor unchanged.

This data is encouraging and suggests that DBS may have a role in the management of primary orthostatic tremor although it remains to be seen whether subsequent studies confirm this report.

There has been a suggestion that the nigro-striatal dopaminergic system may be involved in primary orthostatic tremor (POT), as there are anecdotal reports of patients with POT responding to levodopa and dopamine agonists, the medications used to treat Parkinson’s disease. The nigro-striatal dopaminergic system is located in the brain and is badly damaged in Parkinson’s. Consequently, in Parkinson’s dopamine transporter scans (DaTSCANs) are abnormal.

There is controversy as to whether or not dopamine transporter scans (DaTSCAN) are normal or mildly abnormal in primary orthostatic tremor (POT), which at best responds only partially to a variety of medications; clonazepam being the current initial treatment of choice. One study of people with orthostatic tremor using DaTSCAN showed that there was a dopaminergic deficit in the brain, like in Parkinson’s disease. However, a subsequent study using the same technique found no abnormality. Consequently, Trocello and colleagues performed DaTSCANs on 12 patients with primary orthostatic tremor and 12 healthy age matched control subjects. The results showed no differences between the two groups, indicating that patients with primary orthostatic tremor probably have normal nigro-striatal dopaminergic pathways. As 8 of the 12 patients had a history of orthostatic tremor stretching for over a decade it is likely that this is a correct finding.

Neuropathic tremor:

A peripheral neuropathy occurs when there is damage to the nerves in the limbs. It can be associated with an action tremor and typically occurs in patients with chronic inflammation of their peripheral nerves, where the inflammation damages the myelin coat of the nerves. This is known as a demyelinating neuropathy. The mechanism of the tremor caused by a peripheral neuropathy was first shown by NTF trustee, Dr Peter Bain.

Neuropathic tremor responds poorly to medication and so it is of great interest that recently Breit and colleagues reported the effects of DBS on a 72 year old patient with tremor resulting from a neuropathy. The patient’s tremor was very disabling and did not respond to medication. The patient underwent bilateral ventralis intermedius (Vim) nucleus DBS. This resulted in a 30% improvement in the patient’s tremor that was maintained one year after surgery. However, the patient’s peripheral nerve damage and gait continued to deteriorate and increased stimulation resulted in temporary worsening of speech and gait.

Nevertheless, even though this patient’s response was only partial, the result is still encouraging.

Tremor:

There has been a lot of debate about the pros and cons of DBS compared to thalamotomy (where a small burn is made in the same area of the brain that would otherwise be used for stimulation) for the treatment of tremor.

In 2000 Schuurman and colleagues (a group of Dutch neurologists and neurosurgeons) published the results, obtained six months after surgery, of a study comparing the effects of thalamotomy with thalamic stimulation. Forty-five of these patients had Parkinson’s, thirteen had ET and ten had multiple sclerosis (MS) associated tremor. The results at that time showed that the two procedures were equally effective at decreasing tremor but that thalamic stimulation was associated with greater functional improvement in the patients (i.e. their ability to perform their daily activities).

Recently the same group reported the results obtained five years after surgery from 48 of the original 68 patients. The ‘long term’ results show that thalamic stimulation continued to provide greater functional gains for the patients compared to thalamotomy; although, both thalamotomy and thalamic stimulation procedures suppressed tremors to an equal degree in patients with Parkinson’s.

However, a diminished beneficial effect of DBS over time was detected in 50% of the patients with ET and there was no functional advantage of stimulation over thalamotomy for the ET patients.

A decreased beneficial effect of stimulation over time was also detected in 50% of the patients with MS tremor and stimulation was less effective than thalamotomy at suppressing MS tremor in the long-term.

These long term results are most interesting, as this study shows that further investigation of the long term effects of thalamic lesion surgery (i.e. making a small burn in the thalamus) versus stimulation of the thalamus in patients with disabling ET and MS tremors need to be performed.